1. Field of the Invention
The field of the invention is the manufacture of 18F-labeled radiopharmaceuticals and particularly, the production and use of anhydrous 18F-containing gases for more efficient and cost effective 18F-labeling compounds used in PET imaging.
2. Description of the Related Art
Compounds that are labeled with the radionuclide Fluorine-18 (18F) are used as diagnostic imaging agents in positron emission tomography (PET). For example, 2-[18F]fluoro-2-deoxy-D-glucose (FDG) is one tracer used in PET imaging. This molecule, labeled with 18F, behaves in a way similar to glucose in the first step of its destabilization in the human body and allows a user to map and quantify this fundamental mechanism. It is indicated for diagnosis of numerous diseases. FDG and its preparation are described in U.S. Pat. Nos. 4,617,386, 4,794,178, 5,169,942, 5,264,570, 5,436,325, 5,759,513, 5,808,020, 5,932,178, and 6,172,207.
FDG and many other 18F-labeled compounds are used in clinical PET imaging of human diseases. However, the radiochemical synthesis of such 18F-labeled compounds is often limited by the reactivity of the raw material [18F]fluoride. Specifically, the difficulty in producing [18F]fluoride in an anhydrous form has been a major obstacle to the efficient syntheses of many commonly used PET tracers from tracer precursor compounds.
Conventionally, PET precursor compounds are labeled with 18F using the [18F]fluoride ions produced when the accelerated protons produced by a proton accelerator such as a cyclotron target the 18O atoms in 18O enriched water. The resulting [18F]fluoride ions are dissolved in the water solution, and this water solution cannot be transported long distances without sustaining high losses within the transport tubing.
The current processing methods for preparing and using [18F]fluoride for 18F-labeling of PET tracer precursor compounds are time-consuming, incur loss of radioactivity, and present inflexibility for design of new radiosynthesis paradigms, such as the “chemistry-on-a-chip” model. Furthermore, the conventional model for manufacturing and distributing 18F-labeled compounds, such as FDG, to hospitals for clinical PET imaging has been limited to a centralized distribution scheme whereby networks of PET tracer distributors ship FDG and other tracers to hospitals via trucks as a final product to be administered to patients.
A new “decentralized” distribution model has been proposed by others that entails distributing raw material [18F]fluoride to various PET imaging sites, such as hospitals, wherein each site would have dedicated 18F radiochemistry equipment capable of converting the [18F]fluoride to 18F-products according to a “dose-on-demand” model. This concept has not been put into practice because conventional radiochemistry methods do not efficiently convert [18F]fluoride in water solution into useful 18F-products, such as PET tracer compounds.
Typically, [18F]fluoride is produced in a cyclotron target containing 18O-enriched water, with enrichment of 18O exceeding 95%. In contrast, natural water contains only 0.2% enrichment of 18O. The enrichment process is costly, resulting in high cost for 18O enriched water and the desire to efficiently recycle the enriched water for reuse.
After the proton irradiation of the targeted 18O-enriched water is completed, the resulting [18F]fluoride-containing water is forced by overpressure through Teflon or polypropylene tubing over long distances (20-60 feet) to radiochemistry hot cells, where further radiochemical processing is performed. Because water naturally adheres to the tubing, there are unavoidable losses of [18F]fluoride associated with the transport process. In most facilities, a rinse of the target with either normal water (mainly 16O-water) or 18O-enriched water is performed to obtain a large portion of the adhered [18F]fluoride, but this step has significant disadvantages related to the high cost of 18O-enriched water and the limited cost savings associated with recycling.
The radiochemistry process, which occurs in a separate radiochemistry hot cell, generally begins by separating the [18F]fluoride from the 18O-enriched water, typically using an anion-exchange cartridge. [18F]fluoride is trapped on the cartridge while the 18O-enriched water is collected, stored and returned to the vendor for recycling.
If the target rinse is performed with 18O-enriched water, then the 18O-enrichment of the water remains high, and the material is recycled with minimal cost. However, the cost of the 18O water rinse is substantial (typically more than $125). On the other hand, if normal water is used for the rinse, then the isotopic enrichment of the collected 18O water is compromised such that the collected water will have much less value when sold back to the vendor.
The existing methods for preparing and transporting [18F]fluoride for labeling PET tracer precursor compounds present a number of significant challenges. As noted above, such methods result in significant loss of the [18F]fluoride raw material in transfer lines. Furthermore, significant radioactive decay occurs in the time needed to dry down the 18F in the radiochemistry hot cell. In addition, because of the volume of the 18O-enriched water within which the [18F]fluoride is delivered, current methods limit the potential designs that can be used for radiochemistry processing. For example, microfluidic processing cannot be done with such large volumes (typically greater than 2 mL), and such volumes necessitate using a non-microfluidic 18F dry-down apparatus and procedures. Similarly, transfer of [18F]fluoride used in conventional methods to a microfluidic chip involves significant challenges and large loss of [18F]fluoride. Finally, the existing 18F-labeling technologies often leave the [18F]fluoride in the presence of trace metal ions that hinder its reactivity, thus further decreasing incorporation yields into 18F-labeled radiopharmaceuticals.
Thus, there is a need for improved methods for preparing, transporting, and incorporating 18F-labels into PET tracer precursor compounds to make PET tracer compounds for clinical use.